Trials Open for Enrollment: Phase II Study of VAL-083 in Patients with MGMT-unmethylated Bevacizumab-naïve Recurrent Glioblastoma Multiforme

DelMar has initiated enrollment of a Phase II study of VAL-083 (dianhydrogalactitol) in patients with MGMT-unmethylated, Avastin (bevacizumab)-naïve recurrent glioblastoma.

This trial is being conducted in collaboration with the University of Texas MD Anderson Cancer Center.

To be eligible for the trial, patients must have histologically confirmed GBM with MGMT promoter-unmethylated which has recurred following chemoradiation.

Enrolled patients will receive VAL-083 administered IV for 3 consecutive days at the beginning of every 21-day cycle. Patients will continue to receive VAL-083  for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation. In patients who demonstrate response or stable disease and tolerate therapy, permission to continue treatment beyond 12 cycles will be considered.

Response to VAL-083 treatment will be assessed prior to each treatment cycle. The goal of this Phase 2 clinical trial is to determine if treatment with VAL-083 improves overall survival compared to historical control.

More information about our clinical trial and a list of participating sites

Background:

The prognosis for recurrent GBM is poor, with a median survival of 4 to 6 months and less than a 5% survival rate at 5 years.  Front-line systemic therapy is temozolomide. However, chemo-resistance due to the DNA repair enzyme O6-methylguanine- DNA-methyltransferase (MGMT), which may be present in GBM tumors, has been implicated in poor outcomes in patients with GBM.

VAL-083 (dianhydrogalactitol) is a structurally unique, "first-in- class", small-molecule chemotherapeutic, which means that the molecular structure of VAL-083 is not an analogue or derivative of other small molecule chemotherapeutics approved for the treatment of cancer. Research suggests that VAL-083 crosses the blood-brain barrier and accumulates in brain tumor tissue. VAL-083 has a distinct mechanism of action: bifunctional DNA alkylation at the N7 position of guanine, which is shown to be different from other pharmaceutical treatments approved to treat GBM such as Temodar™ (temozolomide/TMZ), Avastin™ (bevacizumab), CCNU (lomustine) and BCNU (carmustine). This unique mechanism has been demonstrated to overcome chemo-resistance to MGMT in vitro. VAL-083 demonstrates activity in a wide range of cancer cell lines, including pediatric and adult GBM cell lines and GBM cancer stem cells 7 . Notably, prior human clinical studies conducted by the U.S. National Cancer Institute ("NCI") in the late 1970's and early 1980's suggested that VAL-083 had anti-tumor activity in brain tumors, including GBM.

Detailed Description:

Recurrent glioblastoma (GBM) is characterized by a dismal prognosis, with a median overall survival of 6-9 months. While a standard of care is established for the initial treatment of GBM - radiation with concurrent and adjuvant temozolomide chemotherapy - management of recurrent disease remains suboptimal. Treatment options include repeat surgery, re-irradiation, or chemotherapy (including experimental targeted therapies, biologic agents, and immunotherapies). Only a minority of patients respond to these treatments, and the resultant benefits in progression-free and overall survival are on the order of weeks to months.

Prognosis and response to therapy are known to be better in patients with a methylated MGMT promoter gene. Epigenetic silencing of MGMT by promoter methylation is an important factor in predicting outcome for patients with GBM treated with temozolomide. Approximately 66% of GBM tumors are MGMT unmethylated (high expression of MGMT), which through a MGMT repair mechanism, confers resistance to temozolomide, the standard chemotherapy treatment of GBM.

VAL-083, unlike temozolomide or nitrosoureas, is demonstrated to be active independent of MGMT resistance mechanisms, in vitro. Thus, it may provide a treatment option for those patients that are considered likely to be poor responders to temozolomide.

This is a non-comparative, single arm, biomarker-driven study with VAL-083.

Study Eligibility:

Inclusion criteria

  • Patient must willingly provide written consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.
  • Patients must be ≥ 18 years old.
  • Patients must have histologically confirmed initial diagnosis of primary intracranial World Health Organization (WHO) Grade IV malignant glioma (glioblastoma, GBM), now recurrent. Patients with recurrent disease whose initial diagnostic pathology confirmed glioblastoma will not need re-biopsy. Alternately, patients with prior intracranial low-grade glioma or anaplastic glioma will be eligible, if histologic assessment demonstrates transformation to GBM (first diagnosis of secondary GBM).
  • Patients must have radiographic evidence of recurrent/progressive GBM after prior therapy (biopsy or resection and chemoradiation); 1st recurrence of GBM only, per Response Assessment in Neuro-Oncology Criteria (RANO) criteria. Histologically documented transformation from a lower grade gliomas will be considered first recurrence.
  • Patients must have confirmed GBM MGMT status (tumor must be MGMT promoter unmethylated) by central laboratory Clinical Laboratory Improvement Amendments (CLIA) certified testing at MD Anderson, prior to registration. If initial MGMT testing obtained at an outside institution, MGMT status must be centrally retested at MD Anderson.
  • Patients must have Karnofsky Performance Status (KPS) > 60%.
  • Patients must have been previously treated for GBM with radiation with concurrent and adjuvant temozolomide chemotherapy.
  • Adequate recovery from all recent surgery is required. At least 21-days must have elapsed from the time of any major surgery, including craniotomy/tumor resection. Patients must have recovered from all surgery-related toxicities to Grade 1 or less.
  • Patients must ≥ 12 weeks from radiotherapy, to minimize the potential for magnetic resonance imaging (MRI) changes related to treatment (pseudo progression) that might be misdiagnosed as true progression of disease, unless the patient fulfills criteria for early progressive disease by RANO.
  • Prior therapy with gamma knife or other focal high-dose radiation is allowed, but at least 2 weeks must have elapsed from the time of treatment, and the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field.
  • Patients must be at least 4 weeks from last dose of chemotherapy.
  • Patients must be at least 4 weeks or 5 half-lives (whichever is shorter) from the last dose of prior investigational anti-cancer drugs.
  • Patients must have recovered from all treatment-related toxicities to Grade 1 or less.
  • If receiving corticosteroids, patients must be on a stable or decreasing dose of corticosteroids for ≥ 5 days prior to baseline MRI.
  • Patients must have a predicted life expectancy of at least 12 weeks.
  • Patients must have adequate bone marrow and organ function.
  • Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests and accessible for follow-up.
  • If the patient has been using the Optune™ device, it will be discontinued before initiating treatment with either study medication, and per inclusion criterion listed above, the patient must have recovered from all treatment-related toxicities to Grade 1 or less.
  • Pregnancy restrictions - Women of childbearing potential must have a negative B-HCG documented within 7 days prior to registration

Exclusion criteria

  • Within 12 weeks of chemoradiation unless the patient fulfills criteria for early progressive disease by RANO
  • Receipt of investigational agents within 5 half-lives of last dose of investigational agent
  • Concurrent use of other investigational agents or Optune™ device
  • Prior therapy with lomustine
  • Prior therapy with bevacizumab
  • Current history of neoplasm other than the entry diagnosis. Patients with previous cancers treated and cured with local therapy alone may be considered with approval of the PI
  • Evidence of leptomeningeal spread of disease
  • Need for urgent palliative intervention (e.g., impending herniation)
  • Severe, intercurrent illness including, but not limited to unstable systemic disease, including ongoing or active infection, uncontrolled hypertension, serious cardiac arrhythmia requiring medication, or psychiatric illness/social situations that would limit compliance with study requirements
  • Use of medications known to be strong inhibitors of CYP3A4 up to 14 days before Cycle 1 Day 1
  • Patients with a known sensitivity to any of the products to be administered during treatment
  • Patients unable to undergo MRI of the brain
  • Pregnant or breast feeding.

Completed Trials: Open-label, Single Arm, Safety and Tolerability Dose-escalation Study of VAL-083 in Patients with Recurrent Malignant Glioma

DelMar's recently completed a Phase 1/2 an open-label, single arm dose- escalation study designed to evaluate the safety, tolerability, pharmacokinetics and anti-cancer activity of VAL-083 in patients with GBM who have failed both bevacizumab (Avastin™) and temozolomide (Temodar™), unless either or both were contra-indicated.

Data from the trial were presented at the 2016 Annual Meeting of the Society for Clinical Oncology (ASCO). These data demonstrate that a dosing regimen of 40mg/m2/day VAL-083 on days 1-3 of a 21 day cycle was well tolerated in patients with bevacizumab-failed GBM.

Median survival of patients receiving an assumed therapeutic dose of VAL-083 (≥20mg/m2) was 8.35 months following Avastin™ (bevacizumab) failure compared to published literature where survival of approximately two to five months has been reported.

Please click here to view our 2016 ASCO Presentation.

DelMar is currently planning a pivotal, randomized multi-center Phase 3 study measuring survival outcomes compared to a "physicians' choice" control for the treatment of bevacizumab-failed GBM. A summary of the proposed clinical trial design includes:

  • Approximately 180 patients with histologically confirmed recurrent GBM who have failed both standard chemo-radiation and bevacizumab will be randomized in a 2:1 fashion to receive either VAL-083 or a commonly used salvage chemotherapy; The proposed study is projected to be enrolled at approximately 25 centers;
  • The proposed primary endpoint is overall survival (OS);
  • The proposed statistical design between the two arms of the study is 90% power, and is proposed to include an interim analysis at 50% events for futility with O'Brien-Fleming superiority boundary and non-binding, gamma (-5) futility boundary; and
  • The estimated length of the proposed study is less than two years from initiation.
  • The proposed trial design is subject to feedback from the FDA and other regulatory authorities.

Please check back to this page for future updates on this proposed trial.